Our long term goal is to understand adipocyte biology and its physiological relevancy to obesity/ diabetes via examining the molecular controls in adipocytes. Obesity is emerging as an epidemic crisis in the United States and contributes to diabetes, cardiovascular diseases and cancers. Obesity is a consequence of energy imbalance, which leads to elevated lipid accumulation. Physiological and pathological adaptations are involved at obese state to increase lipid storage by adipocytes. Increase in cell size/ mass via hypertrophy is the major pathological adaptation in adipocytes to curb the demand for storage of excess energy. Initial compensatory responses eventually lead to adverse outcomes -- [adipocyte hypertrophy (obesity) J diabetes]. In addition to its obvious role as major depots for excess energy storage, adipose tissue also secret a variety of secretory proteins (adipokines) to regulate energy balance and insulin sensitivity. Dysregulation of adipokine regulation and subsequent pathological adaption leads to severe obesity and insulin resistance. Thus, understanding the molecular controls in adipocytes will provide new insights to obesity and diabetes. Here, we hypothesize that mitogen-activated protein kinase ERK5 contributes to molecular controls in adipocytes. The ERK5 cascade is an evolutionarily conserved pathway involved in hypertrophic signaling. We also found that ERK5 regulates transcription factor NFAT. NFAT mediates expression of several adipokine genes analogous to its role in cytokine expression in immune cells. Notably, both ERK5 and NFAT are involved in hypertrophic response and adipocyte regulation. The role of ERK5 in adipocytes is not known partly due to the lack of knowledge on in vivo physiological substrates of ERK5 and early embryonic lethality of Erk5-/- mice. Using a cre-lox approach, we have generated adipose-specific Erk5-/- mice. The adipose-specific Erk5-/- mice are hyperglycemic and exhibited changes in adipokine profile. Despite increase in fat mass, smaller adipocyte cell size are found in adipose-specific Erk5-/- mice. Mechanistically, we found that deletion of ERK5 affects NFAT, AMPK and PKA signaling pathways. These data indicate that deletion of ERK5 has significant effects in adipocyte signaling, which regulates adipocyte cell size and adipokine expression. To further unravel the role of ERK5 in adipocytes, we will define the physiological role of ERK5 in energy homeostasis (Aim 1). In Aim 2, we will determine the molecular mechanisms of ERK5 in adipocytes. We will also determine the cellular involvement of ERK5 in adipocytes (Aim 3). Completion of this proposal will provide a fundamental basis to advance our understanding of adipocyte regulation and function, in particular on pathological adaptation found in obesity.